ABSTRACT
Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.
Subject(s)
Antiviral Agents/metabolism , COVID-19/pathology , Coronavirus Envelope Proteins/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Apoptosis , COVID-19/complications , COVID-19/virology , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Half-Life , Humans , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutagenesis, Site-Directed , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Spleen/metabolism , Spleen/pathology , Viral Load , Virulence , COVID-19 Drug TreatmentABSTRACT
The COVID-19 epidemic is one of the most influential epidemics in history. Understanding the impact of coronaviruses (CoVs) on host cells is very important for disease treatment. The SARS-CoV-2 envelope (E) protein is a small structural protein involved in many aspects of the viral life cycle. The E protein promotes the packaging and reproduction of the virus, and deletion of this protein weakens or even abolishes the virulence. This review aims to establish new knowledge by combining recent advances in the study of the SARS-CoV-2 E protein and by comparing it with the SARS-CoV E protein. The E protein amino acid sequence, structure, self-assembly characteristics, viroporin mechanisms and inhibitors are summarized and analyzed herein. Although the mechanisms of the SARS-CoV-2 and SARS-CoV E proteins are similar in many respects, specific studies on the SARS-CoV-2 E protein, for both monomers and oligomers, are still lacking. A comprehensive understanding of this protein should prompt further studies on the design and characterization of effective targeted therapeutic measures.